Over the past several years, investigators in this branch have used retroviral gene transfer techniques, antisense strategies, and transgenic mouse models to answer several questions about the biology of the hematopoietic growth factors interleukin 3 and interleukin 6. Recently we have generated a transgenic mouse strains in which the expression of IL3 is abrogated by the expression of an antisense IL3 transcripts. These mice develop a very immature B-cell lymphoproliferation or a neurologic syndrome, and this model may be very useful in elucidating the role of IL3 in immune development and neurologic function. The use of an antisense approach in the transgenic mouse model is novel, and may offer advantages over gene knockout techniques by allowing decreased instead of completely ablated gene expression, especially in models where total knockout is lethal. We have also begun to study the function of gp130 in the murine model system using similar approaches. Gp130 is the nonligand-binding subunit of the IL-6 receptor responsible for signal transduction. this subunit is also part of receptor complexes for other cytokines such as IL-11, LIF, oncostatin M, and CNTF. IL-6 is a major growth factor for murine plasmacytoma and human myeloma cells. IL-6 is supplied by stroma cells to these tumor cells, and we are trying to interrupt this IL6 paracrine tumor support with a soluble gp130 molecule as a candidate inhibitor. Stromal cells we have engineered to produce soluble gp130 can not support the growth of plasmacytoma cell lines, and may offer a possible gene therapy or bone marrow purging approach to myeloma. We are also trying to isolate large quantities of purified soluble gp130 and soluble IL-6 receptor molecules using baculovirus systems in order to be better able to elucidate their true function(s) in the complex IL-6 signaling system. We have also begun to develop an antisense gp130 transgenic mouse model system in order to study the in vivo roles for this ubiquitous and important molecule.